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Publications (7)23.65 Total impact

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    ABSTRACT: Hematopoietic stem cells are key elements for life-long production of mature blood cells. The success of clinical stem cell transplantation may be improved when the number of stem cells that engraft after transplantation can be increased. Here, we investigated in a syngeneic mouse model whether engraftment and reconstitution can be improved by transplantation directly into the bone marrow. In this study, we directly compared syngeneic transplantation of hematopoietic stem cells into the bone marrow with intravenous administration and assessed reconstitution kinetics and engraftment by bioluminescent imaging and chimerism determination. Surprisingly, only about 10% of cells injected directly into the femur (intrafemoral, IF) could be retrieved within 5 minutes after injection. Only in the first 48 hours after transplantation, engraftment in IF-transplanted animals was higher compared with intravenous injection. However, at all later time points no differences could be detected using whole body bioluminescence or measuring blood cell reconstitution. Most importantly, we found that IF-transplanted cells did not outcompete cells transplanted intravenously when cotransplanted in the same recipient. In conclusion, IF transplantation in a murine syngeneic setting revealed no enhanced engraftment. Previous reports on IF transplantation may have relied on escape from immune rejection in xenogeneic or allogeneic models. Therefore, we conclude that stem cells can find the proper microenvironment irrespective of the route of administration.
    Experimental hematology 11/2010; 38(11):1115-23. · 3.11 Impact Factor
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    ABSTRACT: Chronic transplant dysfunction (CTD) is the leading cause for limited kidney graft survival. Renal CTD is characterized by interstitial and vascular remodeling leading to interstitial fibrosis, tubular atrophy and transplant vasculopathy (TV). The origin of cells and pathogenesis of interstitial and vascular remodeling are still unknown. To study graft-versus-recipient origin of interstitial myofibroblasts, vascular smooth muscle cells (SMCs) and endothelial cells (ECs), we here describe a new rat model for renal CTD using Dark Agouti kidney donors and R26 human placental alkaline phosphatase transgenic Fischer344 recipients. This model showed the development of CTD within 12 weeks after transplantation. In interstitial remodeling, both graft- and recipient-derived cells contributed to a similar extent to the accumulation of myofibroblasts. In arteries with TV, we observed graft origin of neointimal SMCs and ECs, whereas in peritubular and glomerular capillaries, we detected recipient EC chimerism. These data indicate that, within the interstitial and vascular compartments of the transplanted kidney, myofibroblasts, SMCs and ECs involved in chronic remodeling are derived from different sources and suggest distinct pathogenetic mechanisms within the renal compartments.
    American Journal of Transplantation 04/2009; 9(3):463-72. · 6.19 Impact Factor
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    ABSTRACT: Previously, we demonstrated potent tumor cell-selective pro-apoptotic activity of scFv425:sTRAIL, a recombinant fusion protein comprised of EGFR-directed antibody fragment (scFv425) genetically fused to human soluble TNF-related apoptosis-inducing ligand (sTRAIL). Here, we report on the promising therapeutic systemic tumoricidal activity of scFv425:sTRAIL when produced by the replication-deficient adenovirus Ad-scFv425:sTRAIL. In vitro treatment of EGFR-positive tumor cells with Ad-scFv425:sTRAIL resulted in the potent induction of apoptosis of not only infected tumor cells, but importantly also of up to 60% of noninfected EGFR-positive tumor cells. A single intraocular injection of Ad-scFv425:sTRAIL in tumor-free nu/nu mice resulted in predominant liver infection and concomitant high blood plasma levels of scFv425:sTRAIL. These mice showed no sign of Ad-scFv425:sTRAIL-related liver toxicity. Identical treatment of mice with established intraperitoneal renal cell carcinoma xenografts resulted in rapid and massive tumor load reduction and subsequent long-term survival. Taken together, adenoviral-mediated in vivo production of scFv425:sTRAIL may be exploitable for systemic treatment of EGFR-positive cancer.
    Molecular Therapy 10/2008; 16(12):1919-26. · 7.04 Impact Factor
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    ABSTRACT: Diabetes is associated with impaired neovascularization leading to reduced revascularization of ischemic tissue and impaired wound healing. Endothelial progenitor cells in diabetes were previously shown to be numerically reduced and functionally impaired. We hypothesize that diabetes also has a long-term effect on angiogenic cells residing in the vessel wall. To test this hypothesis, angiogenic sprout formation from ex vitro cultured aortic rings isolated from diabetic and non-diabetic BioBreeding (BB) rats was assessed. Diabetes prone BB (BBDP) rats spontaneously develop autoimmune diabetes were suboptimally treated with insulin by subcutaneous implantation of slow-release insulin-pellets. Neonatally thymectomized BBDP rats, pre-diabetic BBDP rats and diabetes resistant BBDR rats served as non-diabetic controls. After follow-up thoracic aortas were harvested and cultured in vitro in Matrigel to induce sprout formation. Sprout length was quantified after 4, 7, 10 and 14 days of culture. The total number of sprout-derived cells was measured and in vitro proliferative capacity of sprout cells was quantified. Finally, expression of Flk-1, CD31 and smooth muscle alpha-actin on sprout cells was determined. Mean blood glucose levels in diabetics were significantly elevated compared with non-diabetics. Both long-term and short-term diabetes significantly reduced sprout formation (p<0.05 vs. non-diabetics). Reduced sprout length in diabetics was reflected by significantly reduced numbers of sprout cells that could be isolated (p<0.05 vs. non-diabetics). Isolated sprout cells from diabetics revealed significantly reduced proliferative capacity after in vitro culture (p<0.05 vs. non-diabetics). Immunofluorescent staining indicated an endothelial phenotype of both freshly isolated and in vitro cultured sprout cells as indicated by CD31 and Flk-1 expression and absence of smooth muscle alpha-actin expression. Diabetes in BB rats impairs angiogenic sprouting from cells residing in the vascular wall, independent of effects on circulating cells or circulating angiogenic/anti-angiogenic factors. The angiogenic impairment of diabetic sprout cells is, to some extent, imprinted upon the cells.
    Microvascular Research 05/2008; 75(3):420-5. · 2.93 Impact Factor
  • Cardiovascular Revascularization Medicine. 01/2008; 9(3):204-204.
  • Vascular Pharmacology - VASC PHARMACOL. 01/2006; 45(3).
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    ABSTRACT: We have recently shown that two ATP binding cassette (ABC) transporters are enriched in Lubrol-resistant noncaveolar membrane domains in multidrug-resistant human cancer cells [Hinrichs, J. W. J., K. Klappe, I. Hummel, and J. W. Kok. 2004. ATP-binding cassette transporters are enriched in non-caveolar detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in human multidrug-resistant cancer cells. J. Biol. Chem. 279: 5734-5738]. Here, we show that aminophospholipids are relatively enriched in Lubrol-resistant membrane domains compared with Triton X-100-resistant membrane domains, whereas sphingolipids are relatively enriched in the latter. Moreover, Lubrol-resistant membrane domains contain more protein and lipid mass. Based on these results, we postulate a model for detergent-insoluble glycosphingolipid-enriched membrane domains consisting of a Lubrol-insoluble/Triton X-100-insoluble region and a Lubrol-insoluble/Triton X-100-soluble region. The latter region contains most of the ABC transporters as well as lipids known to be necessary for their efflux activity. Compared with drug-sensitive cells, the detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in drug-resistant cells differ specifically in sphingolipid content and not in protein, phospholipid, or cholesterol content. In drug-resistant cells, sphingolipids with specific fatty acids (especially C24:1) are enriched in these membrane domains. Together, these data show that multidrug resistance-associated changes in both sphingolipids and ABC transporters occur in DIGs, but in different regions of these domains.
    The Journal of Lipid Research 12/2005; 46(11):2367-76. · 4.39 Impact Factor